Who should be considered for treatment

The age-associated decrease in serum testosterone levels raises the issue of androgen substitution in elderly males: who should be treated, how and for how long?

As to the first question, in theory androgen administration to elderly men may be either "substitutive" to alleviate symptoms and prevent complications of a partial or more complete androgen deficiency, or rather "pharmacological" administration to elderly men who are not necessarily androgen deficient, but with specific treatment goals such as prevention or treatment of osteoporosis, frailty, or treatment of erectile dysfunction. Clearly, although there have been a few small-scaled studies providing indications of potential treatment benefits (Gruenewald and Matsumoto 2003), for no single indication does the present evidence even approach justifying "pharmacological" androgen treatment in elderly men. Thus we are left with only "substitutive" treatment to be considered at this time.

Albeit systematic studies on the effects of androgen substitution in younger hypogonadal men are few and randomized trials of substantial duration are not available for evident ethical reasons, it is generally accepted that prolonged androgen deficiency in young men results in symptoms affecting quality of life and carries a risk for longer-term complications; thus intervention to reestablish physiological androgen levels is required unless there is a specific contraindication. As to the elderly, there is no a priori medical or moral justification for withholding the benefits of substitutive treatment from symptomatic hypogonadal elderly men, but a prudent approach is advisable in view of the limited data and clinical experience for this population and of the potential for a greater susceptibility for adverse treatment effects in the elderly.

This brings up the key problem of how to diagnose androgen deficiency in elderly men andwhat their testosterone requirements are (Vermeulen 2001; Vermeulen and Kaufman 2002). If distribution of serum testosterone levels in healthy young men is taken as reference, the question is whether elderly men are equally, less or more sensitive to testosterone action. Any answer to this question is complicated by the fact that, on the one hand, signs and symptoms of androgen deficiency lack specificity, while on the other hand, a useful direct biochemical measure of androgen activity is lacking. Indeed, the more we learn about testosterone action, the more it becomes clear that measures of (total or non-specifically bound) testosterone in the circulation can at best imperfectly reflect the action of testosterone and its bioactive metabolites in the tissues. Moreover, there are clear indications that testosterone requirements for normal functioning may differ widely according to tissue and physiological function, whereas the considerable inter-individual differences in serum testosterone levels seen at all ages may be the expression of individual differences in androgen sensitivity and requirements.

In the absence of a reliable parameter, a pragmatic and sufficiently conservative approach to the diagnosis of androgen deficiency in elderly men should rely on both the clinic and the hormonal levels, diagnosis of androgen deficiency requiring congruent findings of a suggestive clinical picture together with clearly low serum testosterone levels. As to the latter, in the absence of definitive evidence of altered sensitivity to androgens in the elderly, the least arbitrary attitude is to use the same lower normal limit as in young men, i.e. around 11 nmol/l (or 320 ng/dl) for total serum testosterone, around 0.225 nmol/l (or 6.5 ng/dl for serum free testosterone, and around 5 nmol/l (or 145 ng/dl) forbioavailable testosterone. Parameters of the biologically active fraction of serum testosterone, i.e. serum free testosterone and bio-available (i.e. non specifically bound) testosterone, are more appropriate forthe evaluation of the androgen status. Their use will result in classification of an even larger proportion of elderly men as being hypoandrogenic, as the age-dependent decrease is steeper than for total testosterone. On the other hand, in a number of situations with low serum SHBG, such as in obesity and during glucocorticoid treatment, these measurements may reveal an androgen status more favorably preserved than that indicated by serum total testosterone. It is advisable to apply the above cut-off values conservatively and to consider for the diagnosis of deficiency only values that are frankly low. Indeed, whereas reports of decreased tissue concentration of androgen receptors in the elderly (Roehrborn etal. 1987) might suggest decreased sensitivity, the only data from functional studies available indicate an increased sensitivity of LH secretion to the negative feedback action of testosterone in older men (Deslypere etal. 1987, Winters etal. 1984; 1997). Moreover, whereas most studies on administration of testosterone to elderly men have included a large proportion of men with serum testosterone within the lower normal range for young men, probably based on the rationale that these low normal levels might in fact be sub-optimal for many of these particular subjects, the treatment effects were generally disappointing for those men not having clearly low initial serum testosterone levels. As to serum gonadotropin levels, although markedly elevated serum LH certainly adds weight to the finding of decreased serum testosterone and points towards a predominantly testicular factor, elevated serum LH is not a prerequisite for the diagnosis of testosterone deficiency in older men, the age-associated decline of Leydig cell function usually being of mixed testicular and neuroendocrine origin (see section 16.3).

As to the objective signs of relative androgen deficiency, although a decrease of muscle mass and strength and a concomitant increase in central body fat and osteoporosis can most easily be objectified, they are not specific signs. Decreased libido and sexual desire, loss of memory, difficulty in concentration, forgetfulness, insomnia, irritability, depressed mood as well as decreased sense of well-being, are rather subjective feelings or impressions, less easily objectified and certainly difficult to differentiate from hormone-independent aging. Complaints of excessive sweating are not uncommon, whereas true hot flushes do occur in elderly men, although they are mainly prevalent in severe acquired hypogonadism such as under hormonal treatment for prostate cancer.

There exist a number of questionnaires that are being used in clinical or epi-demiological settings to help describe and semi-quantify symptoms in different areas that are of relevance to elderly men, such as questionnaires on self-perceived health status, on depressive mood, on urinary symptoms, on erectile function, or on coping with activities of daily living. Morley et al. (2000) proposed a dedicated instrument, the "ADAM" screening questionnaire for androgen deficiency in aging males. The available information suggests that this questionnaire, although relatively sensitive to detect men with decreased free or bio-available testosterone, lacks the required specificity to be a valid instrument for diagnosis in the individual subject (Delhez etal. 2003). The "Aging Males' Symptoms Scale" (AMS) was developed by Heinemann et al. (1999) in Germany to help describe and quantify the clinical syndrome of'andropause', but was not intended to screen for low serum testosterone and was not validated by the authors against serum androgen levels. Others have reported that this 17 item-questionnaire, which was subsequently linguistically and culturally adapted in several languages, does not allow androgen serum levels in elderly men to be predicted (Dunbar et al. 2001; T'Sjoen et al. 2003). Smith et al. (2000) developed a self-administered 8 item-screener for testosterone deficiency in aging men. Whereas this screener performs better than chance in identifying men with low serum testosterone, mainly it addresses issues of co-morbidity and again lacks the specificity required for a performing clinical tool. From data presently available it does not appear that, albeit helpful in describing symptoms, these questionnaires contribute significantly to the diagnosis of androgen deficiency. Nor is it presently established whether they might serve as a prescreening instrument to select patients for blood sampling; neither is it clear whether screening for low serum testosterone is in itself presently desirable. Indeed, taken the high prevalence in older men of non-specific symptoms loosely associated with hypoandrogenism, spontaneous active reporting of complaints may have the merit of a higher specificity, whereas soliciting complaints with screening questionnaires might lead to over-diagnosis and over-treatment.

In conclusion, according to the present state of the art, androgen supplementation should probably only be considered in the presence of androgen serum levels clearly below the lower normal limit for young men, together with unequivocal signs and symptoms of androgen deficiency, after having excluded reversible causes of low serum androgen and after careful screening for contra-indications. Indeed, the lack of reliable data on the long-term risk-benefit ratio imposes a critical and conservative attitude in accordance with a basic principle of clinical practice, i.e. primum non nocere.

Dealing With Erectile Dysfunction

Dealing With Erectile Dysfunction

Whether you call it erectile dysfunction, ED, impotence, or any number of slang terms, erection problems are something many men have to face during the course of their lifetimes.

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